Existing drugs could help subgroup of patients with osteosarcoma, suggest scientists

A subgroup of patients with osteosarcoma - a form of bone cancer - could be helped by an existing drug, suggest scientists from the Wellcome Trust Sanger Institute and their collaborators at University College London Cancer Institute and the Royal National Orthopedic Hospital NHS Trust. In the largest genetic sequencing study of osteosarcoma to date, scientists discovered that 10 percent of patients with a genetic mutation in particular growth factor signaling genes may benefit from existing drugs, known as IGF1R inhibitors.

The results, published today (23 June) in Nature Communications suggest a re-trial of IGF1R inhibitors for the subset of patients with osteosarcoma who are likely to respond based on their genetic profile.

Osteosarcoma is the most common form of primary bone cancer in children and young adults, usually affecting people aged 10 to 24 years. 160 new patients are diagnosed with osteosarcoma in the UK each year, of which around one-third cannot be cured.

The current treatment for osteosarcoma is chemotherapy followed by surgery, where the bone tumors are removed. There has not been a new treatment for osteosarcoma in almost 40 years, in spite of extensive research.

In the study, scientists analyzed the genome of 112 childhood and adult tumors - double the number of tumors studied previously. In 10 percent of cases, the team discovered cancer-driving mutations in insulin-like growth factor (IGF) signaling genes.

IGF signaling plays a major role in bone growth and development during puberty. Researchers believe that IGF signaling is also implicated in the uncontrollable growth of bone that is characteristic of osteosarcoma.

IGF signaling genes are the target of existing drugs, known as IGF1R inhibitors. Past clinical trials of IGF1R inhibitors as a treatment for osteosarcoma yielded mixed results although occasional patients responded to the treatment. In spite of this, IGF1R inhibitors have not been further tested in osteosarcoma, as it had been unclear who would benefit from the treatment.

Dr. Sam Behjati, first author from the Wellcome Trust Sanger Institute and University of Cambridge, said: "Osteosarcoma is difficult to treat. Despite extensive research over the past 40 years, no new treatment options have been found. In this study we reveal a clear biological target for osteosarcoma that can be reached with existing drugs."

In the study, scientists looked for mutations in the tumors to understand the mechanism of osteosarcoma development. The genetic information revealed a specific process for rearranging the chromosomes that results in several cancer-driving mutations at once.

Professor Adrienne Flanagan, senior author from the Royal National Orthopedic Hospital NHS Trust and University College London Cancer Institute, said: "By sequencing the whole genome of the tumors, we have unpicked the mechanism behind osteosarcoma for the first time. We discovered a new process -- chromothripsis amplification - in which the chromosome is shattered, multiplied and rejigged to generate multiple cancer-driving mutations at the same time. We believe this is why we see very similar osteosarcoma tumors in children and adults, which are not the result of ageing."

Dr. Peter Campbell, lead author from the Wellcome Trust Sanger Institute, said: "Currently, there are no new osteosarcoma treatments on the horizon. Genomic sequencing has provided the evidence needed to revisit clinical trials of IGF1R inhibitors for the subset of patients that responded in the past. The mutations of patients' tumors may enable clinicians to predict who will, and will not respond to these drugs, resulting in more efficient clinical trials. The drugs could be effective for 10 per cent of osteosarcoma patients."

Dr. Atilgan Yilmaz and his team have developed a method by which they can produce haploid human embryonic stem cells from oocytes. They combined this technique with CRISPR-Cas9 to generate an atlas of the genome, containing the functions of over 18,000 genes.

Chi-En Lin won Metrohm’s Young Chemist of the Year award for his research into optimal biomarker frequencies, not just the novelty of the research but how it can be applied. Determining optimal biomarker frequencies for multimarker biosensors has wide ranging uses from rapid cancer screening methodologies, dry diagnostics, providing personalized medicine and helping to detect comorbidities before they become a problem.

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